Related Experiment Video
Updated: Apr 2, 2026
14:57
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
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The Moving Target: Cis-Mutation-Driven Resistance to p53-Y220C Reactivator
Yanqing Liu1, Wei Gu1,2
1Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
Cancer Discovery
|April 1, 2026
Summary
Rezatapopt resistance in the PYNNACLE trial arose from new TP53 mutations. These secondary mutations in the Y220C-mutant background reduced the drug
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The p53 protein is a critical tumor suppressor. Mutations in TP53, including Y220C, are common in various cancers.
- Rezatapopt is a novel therapeutic agent designed to reactivate p53 with the Y220C mutation.
Purpose of the Study:
- To investigate the mechanisms of resistance to rezatapopt observed in the PYNNACLE clinical trial.
- To identify genetic alterations that confer resistance to p53-Y220C reactivation therapy.
Main Methods:
- Genomic analysis of patient samples from the PYNNACLE trial.
- Sequencing of the TP53 gene in tumors exhibiting rezatapopt resistance.
Main Results:
- Rezatapopt treatment selected for secondary mutations within the TP53 gene in patients with the Y220C mutation.
- These acquired TP53 mutations abrogated the therapeutic efficacy of rezatapopt, leading to treatment resistance.
Conclusions:
- Secondary TP53 mutations are a key mechanism of acquired resistance to rezatapopt.
- Understanding these resistance mechanisms is crucial for developing future strategies for p53-targeted therapies.
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